Aqueous lubrication solutions have widespread use in ophthalmic surgery as protective agents for the easily damaged intraocular tissues. A major concern in ophthalmic surgery has been the frequent observation of elevated intraocular pressure associated with the surgical use of viscoelastic solutions. Elevated intraocular pressure can reduce the flow of blood-born oxygen and nutrients to the eye and to the optic nerve. Not surprisingly, such elevated pressure is strongly correlated with loss of vision (glaucoma). It is, thus, desirable that solutions for ophthalmic surgery be easily removed from eye tissues by irrigation and aspiration. It is further desirable that any residues remaining in the eye show reduced tendency to induce elevated ocular pressure.
A number of solutions have been used or proposed for use as viscoelastic solutions These include solutions of sodium hyaluronate (Healon .TM., Phamacia LKB Biotechnology, Inc. and Amvisc.TM., IOLAB); chondroitin sulfate; mixtures with chondroitin sulfate with sodium hyaluronate (Viscoat.TM., Cooper-vision/ALCON); methylcellulose; carboxymethylcellulose; polyacrylamide or polymethacrylamide; and collagen derivatives. A number of these solution are reviewed by Arshinoff, Curr. Can. Ophthalmic Prac. 4:64-74, 1986.
Sodium hyaluronate solutions are the most widely used viscoelastic solutions for ophthalmic surgery Balazs (U.S. Pat. No. 4,141,973) or Pape (U.S. Pat. No. 4,328,803) describe their manufacture and/or use. These solutions, however, have been found to induce transient elevations in intraocular pressure. They have the further disadvantage of being expensive and failing to adhere to ocular prostheses and surgical instruments.
Chondroitin sulfate solutions are not pseudoplastic (and not viscoelastic) and consequently are difficult to inject through the narrow gauge needles used in ophthalmic surgery (see MacRae et al., "The Effects of Sodium Hyaluronate, Chondroitin Sulfate and Methyl Cellulose on the Corneal Endothelium and Intraocular Pressure," Amer. J. Ophthal. 95:332-341, 1983). Additionally, these solutions are less effective than sodium hyaluronate solutions in maintaining space between separated ocular tissues Finally, such solutions are associated with sharp elevations in intraocular pressure.
Unmodified collagen is usually unsuitable for ophthalmic solutions due to its low solubility at pH values close to neutral pH. However, Devore et al. (U.S. Pat. Nos. 4,713,446 and 4,851,513) and Miyata et al. (U.S. Pat. No. 4,748,152) have developed collagen-based viscoelastic solutions wherein the collagen is derivatized at lysyl amino acids to increase its solubility at neutral pH.
Miyata et al. (supra) teach partially succinylated ateleopeptide collagen dissolved in physiologic saline. The viscosities taught therein are modest (highest is 10,000 centipoise for a 3% solution). Miyata et al. have no teachings relating to a collagen solution that is readily irrigated out of eye tissues. Nor are there any disclosures in Miyata et al. of the effects of the solution on intraocular pressure.
Devore et al. (supra) teach a method of producing collagen suitable for viscoelastic solutions by acylating the lysyl amino acids of collagen with a combination of monofunctional and bifunctional reagents. The result of this acylation treatment is that some collagen lysine amino groups are modified to substitute a carboxylic acid group in place of the basic amino function. The residue of the lysine amino groups are covalently linked to lysine amino groups of the same or an adjacent collagen molecule. The viscoelastic solution is produced by reconstituting this derivatized collagen in a physiologic saline solution. These are no disclosures in the Devore et al. patents of collagen viscoelastic solutions that are readily irrigated out of ocular cavities. Neither is there any disclosure of the effects of the collagen solutions taught therein on intraocular pressure.
Desirable properties of viscoelastic solutions include: transparency; stability (i.e. they maintain their useful properties over long term storage); high viscosity; pseudoplastiticity; viscoelasticity; thixotropy; and biological compatibility.
Pseudoplastic solutions are useful in visco-surgery because their viscosity drops when they are subjected to high shear flow, such as occurs during injection through the high gauge (narrow) needles used in ophthalmic surgery. (Pseudoplastic fluids are non-Newtonian fluids wherein the kinetic viscosity (centipoise-sec or cps) decreases as the sheer rate increases.) Thus, pseudoplastic surgical solutions are injectable despite their viscosity.
Viscous solutions are useful due to their tendency to resist flowing out of the ocular cavity into which they have been injected.
Viscoelastic solutions are useful in viscosurgery because they resist having their shape deformed (i.e., they are elastic), thus helping to maintain the shape of body cavities into which the solutions are injected. (The elasticity of the solution results in the Weissenberg Effect, which describes the tendency of viscoelastic solutions to flow at right angles to an applied force.) During surgery, viscoelastic materials protect cell and tissue surfaces from mechanical trauma; create space by separating two adjacent but not adherent tissue surfaces, or by breaking normal or pathological tissue adhesions; maintain space, for instance, in the interior chambers of the eye or in the lens sack, allowing for safe surgical manipulations by permitting the insertion of implants without dislocating or touching sensitive tissues; contain hemorrhages; and also act as a "soft instrument" or "surgical tool" to move, manipulate or relocate tissues.
Following injection of a viscoelastic solution, at high shear, through a narrow gauge needle (e.g. into a chamber of the eye), it is useful for the solution to regain the majority of its viscosity. Solutions having this recovery property are "thixotropic."
A biocompatible substance, as used herein, shall be noninflammatory, nontoxic, nonimmunogenic, pH buffered and shall have osmolarity between about 200 milliosmoles and about 400 milliosmoles, preferably between about 250 milliosmoles and about 350 milliosmoles, most preferably between about 280 milliosmoles and about 330 milliosmoles.
What is needed in the art is a viscoelastic solution that has transparency, stability, high viscosity, pseudoplasticity, viscoelasticity, thixotropy, and biological compatibility, but moreover, can be used in ophthalmic surgery with reduced risk of elevated intraocular pressure.